High Ro52 Expression in Spontaneous and UV-Induced Cutaneous Inflammation

Oke, Vilija; Vassilaki, Ismini; Espinosa, Alexander; Strandberg, Linn; Kuchroo, Vijay K.; Nyberg, Filippa; Wahren‐Herlenius, Marie

doi:10.1038/jid.2008.453

Cited by 59 publications

(43 citation statements)

References 32 publications

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“…Spontaneous SLE has been linked to alterations in expression (57) and activation of TLR7/9 (17, 18), dysregulation of the cytosolic sensors p202 and AIM2 (24,25), and polymorphisms (21) and heightened expression in TRIM21 (22). We now define that defective degradation of FcγR-bound cargo in the lysosome is a critical upstream event that overburdens the phagolysosome.…”

Section: Discussionmentioning

confidence: 99%

“…Polymorphisms in the sensor that recognizes cytoplasmic IgG (tripartite motif containing 21; TRIM21; ref. 21), and heightened expression of TRIM21 (22) and its regulated genes (22,23), have been identified in SLE patients. Further, two cytosolic sensors that recognize dsDNA (p202 and absent in melanoma 2; AIM2) have been implicated in type 1 interferon (IFN) production in murine lupus (24,25).…”

mentioning

confidence: 99%

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Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Monteith

Kang

Scott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Defects in clearing apoptotic debris disrupt tissue and immunological homeostasis, leading to autoimmune and inflammatory diseases. Herein, we report that macrophages from lupus-prone MRL/lpr mice have impaired lysosomal maturation, resulting in heightened ROS production and attenuated lysosomal acidification. Impaired lysosomal maturation diminishes the ability of lysosomes to degrade apoptotic debris contained within IgG-immune complexes (IgG-ICs) and promotes recycling and the accumulation of nuclear self-antigens at the membrane 72 h after internalization. Diminished degradation of IgG-ICs prolongs the intracellular residency of nucleic acids, leading to the activation of Toll-like receptors. It also promotes phagosomal membrane permeabilization, allowing dsDNA and IgG to leak into the cytosol and activate AIM2 and TRIM21. Collectively, these events promote the accumulation of nuclear antigens and activate innate sensors that drive IFNα production and heightened cell death. These data identify a previously unidentified defect in lysosomal maturation that provides a mechanism for the chronic activation of intracellular innate sensors in systemic lupus erythematosus.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Monteith

Kang

Scott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A large number of TRIM genes are induced by type I or type II IFNs (e.g., during viral or bacterial infections) (20,21). Interestingly, some TRIM genes are also overexpressed in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, suggesting that TRIM proteins participate in the pathogenesis of these diseases (22)(23)(24). Trim21 is induced by both type I and type II IFNs and is overexpressed in patients with systemic lupus erythematosus and Sjögren's syndrome compared with healthy controls (23,24).…”

Section: /2mentioning

confidence: 99%

“…Interestingly, some TRIM genes are also overexpressed in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren's syndrome, suggesting that TRIM proteins participate in the pathogenesis of these diseases (22)(23)(24). Trim21 is induced by both type I and type II IFNs and is overexpressed in patients with systemic lupus erythematosus and Sjögren's syndrome compared with healthy controls (23,24). The molecular mechanisms regulating Trim21 expression are unknown, but because Trim21 is induced by IFNs we hypothesized that transcription factors activated by IFN signaling control Trim21 expression.…”

Section: /2mentioning

confidence: 99%

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Sjöstrand

Ambrosi

Brauner

et al. 2013

The Journal of Immunology

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Tripartite-motif 21 (TRIM21) is an E3 ubiquitin ligase that regulates innate immune responses by ubiquitinating IFN regulatory factors (IRFs). TRIM21 is mainly found in hematopoietic cells in which its expression is induced by IFNs during viral. infections and in systemic autoimmune diseases such as systemic lupus erythematosus and Sjögren’s syndrome. However, the exact molecular mechanism by which the expression of the Trim21 gene is regulated is unknown. In this study, we demonstrate that IFNs induce Trim21 expression in immune cells via IRFs and that IFN-α and IFN-β are the most potent inducers of Trim21. A functional IFN-stimulated response element but no conserved IFN-γ–activated site was detected in the promoter of Trim21. IRF1 and IRF2 strongly induced Trim21 expression in an IFN-stimulated response element–dependent manner, whereas IRF4 and IRF8 strongly repressed the IRF1-mediated induction of Trim21. Consistent with this observation, baseline expression of Trim21 was elevated in Irf4−/− cells. TRIM21, IRF1, and IRF2 expression was increased in PBMCs from patients with Sjögren’s syndrome compared with healthy controls. In contrast, IRF4 and IRF8 expression was not increased in PBMCs from patients. The IFN-γ–mediated induction of Trim21 was completely abolished by inhibiting protein synthesis with cycloheximide, and Trim21 expression could not be induced by IFN-γ in Irf1−/− cells, demonstrating that IFN-γ induces Trim21 indirectly via IRF1 and not directly via STAT1 activation. Our data demonstrate that multiple IRFs tightly regulate expression of Trim21 in immune cells, suggesting that a well-controlled expression of the E3 ligase TRIM21 is important for regulation of immune responses.

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“…24 Meanwhile this testing regimen has received much attention because phototesting is not only an optimal way to evaluate photosensitivity in patients with CLE, but the reproducibility of inducing skin lesions by UVA and UVB irradiation makes it an ideal model for several experimental approaches, which allow the study of inflammatory and immunologic events that take place before and during lesion formation. [25][26][27][28] Most interestingly, the phototesting studies showed that the development of skin lesions in patients with CLE is characterized by a latency period for up to 3 weeks in contrast to other photodermatoses, such as polymorphous light eruption (PLE). 24 Therefore, most patients with CLE are not aware of the link between sun exposure and their disease and deny any effect of UV irradiation on the induction or outcome of their cutaneous lesions.…”

mentioning

confidence: 99%

Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: A randomized, vehicle-controlled, double-blind study

Kuhn

Gensch

Haust

et al. 2011

Journal of the American Academy of Dermatology

108

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High Ro52 Expression in Spontaneous and UV-Induced Cutaneous Inflammation

Cited by 59 publications

References 32 publications

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus

Expression of the Immune Regulator Tripartite-Motif 21 Is Controlled by IFN Regulatory Factors

Photoprotective effects of a broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus erythematosus: A randomized, vehicle-controlled, double-blind study

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